Effects of meditation on physiological and metabolic parameters in patients with type 2 diabetes mellitus "MindDM": study protocol for a randomized controlled trial.

BACKGROUND: Sri Lanka is faced with the challenge of managing a large population with diabetes mellitus by 2030. Psychological stress plays a major role in disease outcome by exerting physiological, psychological and social effects on individuals with chronic disorders. Meditation-based interventions have positive effects on the management of stress and diabetes, which are mediated via modulation of neuro-humoral mechanisms and autonomic functions, among others. Mechanisms of bio-physiological effects of meditation are considered to be through reduction of stress hormones, improvement of insulin resistance and improvement of autonomic dysfunction. METHODS: This study will be conducted as an open-label, randomized controlled clinical trial in the Faculty of Medicine, University of Colombo. The aim is to investigate the effects of meditation on glycaemic control and possible mechanisms of how meditation affects glycaemic control in patients with type 2 diabetes. The study was approved by the Ethics Review Committee of the Faculty of Medicine, University of Colombo (ERC/2019/094). Patients who are attending the professorial unit medical clinic with type 2 diabetes (172 in total) will be recruited based on inclusion-exclusion criteria. Patients who have never meditated or rarely meditated (less than once every three months) will be randomized using block randomization to meditation and waitlisted arms (1:1 allocation ratio). The meditation arm will undergo a mindfulness meditation program (selected after studying several meditation methods) conducted by a qualified instructor weekly for a period of 12 weeks in addition to usual care, while the waitlisted arm will only receive usual care. Daily meditation practices will be recorded in a diary. The primary outcome measure is HbA1c. Secondary outcome measures are fasting blood sugar, fructosamine, insulin resistance (calculated using fasting serum insulin), 24-h urinary cortisol, body mass index, cardiac autonomic reflex testing (Ewing's battery of tests) and orocecal transit time using hydrogen breath analysis. All these will be done prior to commencement of the intervention and after 3 months in both arms. Data will be analysed using SPSS V-23. DISCUSSION: This study aims to identify the effect of mindfulness meditation on glycaemic control and the possible mechanisms (neuro humoral and autonomic functions) by which beneficial effects are mediated. TRIAL REGISTRATION: Registered under Sri Lanka Clinical Trial Registry: SLCTR/2021/015 The Universal Trial Number (UTN) U1111-1266-8640.

WHO/INRUD Core drug use indicators and commonly prescribed medicines: a National Survey from Sri Lanka.

BACKGROUND: Identification of internationally comparable indicators of medicines use are important for a country to implement strategies and regulations to improve usage of medicines. Sri Lanka established a new National Medicines Regulatory Authority in 2015 and this survey evaluated the medication use indicators in Sri Lanka, according to the International Network on Rational Use of Drugs (INRUD), prior to its implementation. METHODS: This descriptive-cross-sectional study was conducted in 80 pharmacies, representing all 25 districts of the country. Three pharmacy categories were included; privately owned pharmacies, 'Rajya Osusala' pharmacies operated by the State Pharmaceuticals Corporation (SPC) of Sri Lanka and SPC Franchisee pharmacy outlets. Selection of pharmacies from respective districts were done proportionate to estimated population. Data were collected to identify WHO/INRUD core drug use indicators and the commonly prescribed medicines. RESULTS: Total of 2328 prescriptions were included ('Rajya Osusala 559; SPC Franchise 711; private pharmacies 1058). Altogether 7,255 medicines were prescribed, and the 3 most commonly prescribed medicines were atorvastatin, losartan and metformin. Average number of medicines per encounter was 3.1±1.9 (Median: 3; range 1-12) Highest average number of medicines per encounter was reported in prescriptions received at 'Rajya Osusala' pharmacies (3.6±2.2), significantly higher than in other categories of pharmacies (p<0.001). Percentage of medicines prescribed by generic name was only 35.5%, highest at the 'Rajya Osusala' pharmacies (40.6%), significantly higher than other categories of pharmacies. The overall percentage of medicines prescribed from essential medicine list (EML) was 68.8%, without any significant variation between different categories of pharmacies. The percentage of medicines actually dispensed and accurately labelled were 92.4 and 98.5% respectively. CONCLUSIONS: The average number of medicines per encounter was higher than the WHO recommended value but the usage of antibiotic and injectable drugs were within recommended standards. Generic prescribing, was very much lower. The EML prescribing, labelling and percentage dispensed medicines fared much better although lower than the WHO recommended 100% compliance. This island wide study has provided national wide data before the implementation of key changes in regulation of medicines in Sri Lanka and a repeat survey will be useful to identify impact of the new legislations.

The impact of propranolol on nitric oxide and total antioxidant capacity in patients with resistant hypertension-evidence from the APPROPRIATE trial.

OBJECTIVES: The objective was to assess the effect of propranolol on oxidative stress and anti-oxidant potential in patients with resistant hypertension as a secondary analysis of the APPROPRIATE trial. This randomized double blinded clinical trial recruited patients with resistant hypertension and allocated forty patients to propranolol and placebo in 1:1 ratio. The pro-oxidant state (nitrate and nitrite) was assessed using modified Griess assay. The total anti-oxidant capacity was measured using ABTS assay. RESULTS: Analysis was performed for 18 patients from the propranolol group and 15 from the placebo group. A decline in end point ambulatory blood pressure (p = 0.031) and greater mean reduction in office SBP (29.7 ± 13.0 mmHg, p = 0.021) was noted in the propranolol arm. Nitrate and nitrite levels were lower at the end of a 90 day follow up period in both arms, with a greater mean reduction with propranolol. A significant increase in the AOC was noted in both arms with higher incremental value with Propranolol. The findings of this study do not demonstrate a statistically significant effect of propranolol on the oxidative stress/antioxidant balance in patients with resistant hypertension. The observed trends merit further evaluation.

Regulatory requirements for the registration of generic medicines and format of drug dossiers: procedures in Sri Lanka in comparison with selected regulatory authorities.

BACKGROUND: The regulatory requirements for approval of generic medicines and the format of compiling drug dossiers vary among regulatory authorities. The variation is particularly wide between High-income countries (HIC) and lower and middle-income countries (LMIC) with different regulatory frameworks. In this study, document requirements for approval of generic products, approval timelines, and consideration of bioequivalence and/or biowaiver data by Regulatory Authorities (RAs) of 10 selected jurisdictions was studied. METHODS: The guidelines and procedures from 5 purposively chosen RA of HIC and4 regional RAs relevant for Sri Lanka were compared with the Sri Lankan National Medicines Regulatory Authority (NMRA). Information available in the official websites of the selected RAs, published journal articles and via personal communication was collected in2016. Drug approval timelines achieved in Sri Lanka was obtained from data available from another study. RESULTS: Common technical dossier (CTD) format of the International Council on Harmonization (ICH) for registration of pharmaceuticals (ICH:CTD) or the Association of South East Asian Nations (ASEAN) CTD format (ACTD) was used by all RAs studied except Sri Lanka which use its own dossier format. Nine out of ten RAs studied request BE data or justification for not submitting BE data for generic medicines. Sri Lanka requested BE studies only for antimicrobials, antiepileptic drugs and narrow therapeutic index drugs. Biowaivers are allowed for Biopharmaceutics Classification System (BCS)-based Class 1drugs in Singapore and India. USA, EMA, Canada and South Korea allowed biowaiver for BCS Class1and Class 3drugs but Sri Lanka does not accept BW at present. Nine NMRAs out of the ten studied reported legislated timelines for approval of generic pharmaceuticals except Sri Lanka. CONCLUSIONS: Streamlining the drug regulatory systems in LMIC such as Sri Lanka with that of HIC would facilitate an effective drug regulatory system based on reliance on decisions made by stringent regulatory authorities. Findings of this study encourage Sri Lanka to adopt a CTD format for regulatory submission of drug dossiers. Expanding the BE requirement drug list and accepting BCS-based biowaivers for BSC class 1 and 3 drugs during registration of generic drugs when it is scientifically justified is also recommended for Sri Lanka.

Translation and Validation of the Sinhalese Version of the Brief Medication Questionnaire in Patients with Diabetes Mellitus.

BACKGROUND: Adherence to long-term therapy for diabetes remains low. Accurately measuring adherence is the primary step in improving adherence. We translated and validated the Sinhalese version of the Brief Medication Questionnaire (BMQ) in patients with diabetes. METHODS: The study was conducted at the National Hospital of Sri Lanka between April and December 2017, including 165 patients with diabetes. BMQ was translated into Sinhalese using the translation-back translation method. The translated questionnaire validation included evaluation of internal consistency, temporal stability, and performance in regard to a gold standard (HbA1c). RESULTS: Mean age (±SD) was 60.6 ± 11.1 years, and 46.1% were males. Mean duration of diabetes in the participants was 13.4 ± 7.8 years. Mean HbA1c was 8.3 ± 1.7%, with poor glycaemic control (HbA1c ≥ 8.5%) identified in 41.8%. Medication adherence measured by the BMQ regimen, belief, and recall screens were 39.4%, 75.8%, and 18.8%, respectively. In the analysis of temporal stability, the overall BMQ and the regimen, belief, and recall screens demonstrated good concordance between test and retest with significant gamma correlation coefficients of r = 0.85 (p < 0.001), r = 0.81 (p < 0.001), r = 0.84 (p < 0.001), and r = 0.91 (p < 0.001), respectively. The overall BMQ had a Cronbach α coefficient of 0.65 (95% CI: 0.61-0.70). The questionnaire performance with regards to the gold standards for the overall BMQ AUC was 0.73 (95% CI 0.65-0.80), while the BMQ regimen screen AUC was 0.61 (95% CI 0.53-0.70). The overall BMQ score with a cutoff value of 2 presented better equilibrium between sensitivity and specificity for the gold standard. Those with low adherence had a significantly higher percentage of poor glycaemic control (HbA1c ≥ 8.5%). CONCLUSION: The translated questionnaire demonstrated good reliability (internal consistency), temporal stability (test-retest reliability), and validity when assessed using a gold standard for disease control. Using culturally validated tools to evaluate adherence may help clinicians to identify low adherence and institute corrective measures.

Corticosteroids in management of anaphylaxis; a systematic review of evidence.

SUMMARY: As anaphylaxis is a medical emergency, there are no randomized controlled clinical trials on its emergency management. Therefore, current guidelines are mostly based on data from observational studies, animal and laboratory studies. Although epinephrine is the mainstay of recommended treatment, corticosteroids are also frequently used. This review evaluates the evidence on the use of corticosteroids in emergency management of anaphylaxis from published human and animal or laboratories studies. Thirty original research papers were found with 22 human studies and eight animal or laboratory studies. The average rate of corticosteroid use in emergency treatment was 67.99% (range 48% to 100%). Corticosteroids appear to reduce the length of hospital stay, but did not reduce revisits to the emergency department. There was no consensus on whether corticosteroids reduce biphasic anaphylactic reactions. None of the human studies had sufficient data to compare the response to treatment in different treatment groups (i.e. corticosteroids, epinephrine, antihistamines). Animal studies demonstrated that corticosteroids act through multiple mechanisms. These modulate gene expression, with effects becoming evident 4 to 24 hours after administration. A much quicker response has been detected within 5 to 30 minutes, through blockade of signal activation of glucocorticoid receptors independent of their genomic effects. Therefore, we conclude that there is no compelling evidence to support or oppose the use of corticosteroid in emergency treatment of anaphylaxis. However, based on the available data, it appears to be beneficial and there was no evidence of adverse outcomes related to the use of corticosteroids in emergency treatment of anaphylaxis.

Addition of Propranolol in Resistant Arterial hypertension Treatment (APROPRIATE study): study protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Resistant hypertension is defined as an uncontrolled blood pressure despite treatment at best-tolerated doses with at least three antihypertensive agents including a diuretic. It is an emerging public health problem. At present clinical trial data on management of resistant hypertension is limited. Management is largely based on observational studies and expert opinions. Propranolol is a nonselective beta blocker. Several studies have confirmed that propranolol has a significant hypotensive action, both when used alone and as an adjuvant therapy. At present there are no prospective, randomized, clinical studies evaluating the effectiveness of propranolol in patients with resistant hypertension. Therefore, we have designed a prospective randomized trial to evaluate the safety and efficacy of propranolol in patients with resistant hypertension. METHODS/DESIGN: The study will be conducted as a randomized, double-blind, placebo-controlled clinical trial for a period of 3 months. The study has been approved by the Ethics Review Committee of the Faculty of Medicine, University of Colombo. A total of 200 adults with resistant hypertension will be recruited for the study. They will be randomly assigned to the test and placebo groups on a 1:1 ratio. The test group will receive propranolol 40 mg three times a day and the control group will receive an identical placebo capsule. The study drugs will be double blinded to both investigators and subjects. The visits and the evaluations will be done as follows: screening (visit 0), 1 month (visit 1), 2 months (visit 2) and 3 months (visit 3). The primary outcomes of the study is to find a statistically significant difference between the fall in mean systolic and mean diastolic blood pressure measured by ABPM (ambulatory blood pressure monitoring) from baseline between the two groups. Data will be analyzed using SPSS v16. DISCUSSION: To our knowledge this is one of the first randomized controlled trials evaluating the effects of propranolol in resistant hypertension. This study will provide the necessary groundwork for future large-scale, multicentered clinical trials. The result, positive or negative, should provide a step change in the evidence guiding current and future policies regarding treatment of resistant hypertension. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry, identifier: SLCTR/2016/002 . Registered on 27 January 2016; Study protocol version 2.1.

Effects of Zinc supplementation on serum lipids: a systematic review and meta-analysis.

Zinc is a mineral that plays a vital role in many biological processes and plays an important role in insulin action and carbohydrate metabolism. It may also have a protective role in the prevention of atherogenesis. Numerous studies have evaluated the effects of Zinc supplementation on serum lipids in humans and have demonstrated varying results. We systematically evaluated the literature and performed a meta-analysis on the effects of Zinc supplementation on serum lipids. A five staged comprehensive search of the literature was conducted in the following databases; PubMed, Web of Science and SciVerse Scopus for studies published before 31st December 2014. All controlled clinical trial in humans, that included a Zinc supplement intervention, either alone or in combination with other micronutrients and evaluated effects on serum lipids (total cholesterol [TC], triglycerides [TG], LDL cholesterol [LDL-c] and HDL cholesterol [HDL-c]). A meta-analysis of selected studies was performed using RevMan v5.3. The Jaded scale was used to assess the methodological quality of the trials included in the systematic review. A total of 24 studies were included in Meta analysis, which included a total of 33 Zinc interventions, in a total of 14,515 participants in the Zinc intervention or control group. The duration of Zinc supplementation ranged from 1 month to 7.5 years. The dose of elemental Zinc supplemented ranged from 15-240 mg/day. The pooled mean difference for TC between Zinc supplemented and placebo groups from random effects analysis was -10.92 mg/dl (95 % CI: -15.33, -6.52; p < 0.0001, I(2) = 83 %), while for HDL cholesterol it was 2.12 mg/dl (95 % CI: -0.74, 4.98; p = 0.15, I(2) = 83 %). The pooled mean difference for LDL-c between Zinc supplemented and placebo group from random effect analysis was -6.87 mg/dl (95 % CI: -11.16,-2.58; p < 0.001, I(2) = 31) and for TG it was -10.92 mg/dl (95 % CI: -18.56, - 3.28; p < 0.01, I(2) = 69 %). In conclusion, Zinc supplementation has favourable effects on plasma lipid parameters. Zinc supplementation significantly reduced total cholesterol, LDL cholesterol and triglycerides. Therefore it may have the potential to reduce the incidence of atherosclerosis related morbidity and mortality.

Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis.

The number of people with diabetes and pre-diabetes are exponentially increasing. Studies on humans have shown the beneficial effects of Zinc supplementation in patients with diabetes. The present study aims to systematically evaluate the literature and meta-analyze the effects of Zinc supplementation on diabetes. A systematic review of published studies reporting the effects of Zinc supplementations on diabetes mellitus was undertaken. The literature search was conducted in the following databases; PubMed, Web of Science and SciVerse Scopus. A meta-analysis of studies examining the effects of Zinc supplementation on clinical and biochemical parameters in patients with diabetes was performed. The total number of articles included in the present review is 25, which included 3 studies on type-1 diabetes and 22 studies on type-2 diabetes. There were 12 studies comparing the effects of Zinc supplementation on fasting blood glucose in patients with type-2 diabetes. The pooled mean difference in fasting blood glucose between Zinc supplemented and placebo groups was 18.13mg/dl (95%CI:33.85,2.41; p<0.05). 2-h post-prandial blood sugar also shows a similar distinct reduction in (34.87mg/dl [95%CI:75.44; 5.69]) the Zinc treated group. The reduction in HbA1c was 0.54% (95%CI:0.86;0.21) in the Zinc treated group. There were 8 studies comparing the effects of Zinc supplementation on lipid parameters in patients with type-2 diabetes. The pooled mean difference for total cholesterol between Zinc supplemented and placebo groups was 32.37mg/dl (95%CI:57.39,7.35; p<0.05). Low-density lipoprotein cholesterol also showed a similar distinct reduction in the Zinc treated group, the pooled mean difference from random effects analysis was 11.19mg/dl (95%CI:21.14,1.25; p<0.05). Studies have also shown a significant reduction in systolic and diastolic blood pressures after Zinc supplementation. This first comprehensive systematic review and meta-analysis on the effects of Zinc supplementation in patients with diabetes demonstrates that Zinc supplementation has beneficial effects on glycaemic control and promotes healthy lipid parameters. Further studies are required to identify the exact biological mechanisms responsible for these results.

Familial amyloid polyneuropathy in a Sri Lankan family.

A woman who presented with features of peripheral sensory, motor and autonomic neuropathy and amyloid deposits in the vitreous due to familial amyloid polyneuropathy (FAP) is described. Her father had died of a similar illness and one of her brothers and her two children had lesions suggestive of early amyloid deposits in the vitreous. Reports of familial amyloidosis are rare from Asian countries and it has not been reported in Sri Lanka previously.